Resistance to trophic neurite outgrowth of sensory neurons exposed to insulin

Autor: Yongqin Xu, Bhagat Singh, Jose A. Martinez, Vandana Singh, Douglas W. Zochodne, Anand Krishnan, Todd McLaughlin
Rok vydání: 2012
Předmět:
Zdroj: Journal of Neurochemistry. 121:263-276
ISSN: 0022-3042
Popis: J. Neurochem. (2012) 121, 263–276. Abstract Insulin offers trophic support through receptors expressed widely on peripheral neurons. In this work, we studied whether peripheral sensory neurons demonstrate resistance to its trophic properties, a property relevant during type 2 diabetes mellitus or following supraphysiological therapy. Insulin receptors were not only localized to neuronal membranes and cytoplasm but also had a unique, previously unrecognized localization to neuronal nuclei. We confirmed that nanomolar doses increased neurite outgrowth of adult sensory neurons, but in response to micromolar doses of insulin, even following a brief 2-h exposure, survival and outgrowth of neurites were blunted. Neurons exposed to picomolar insulin concentrations in their media for 5 days had resistance to the impact of later nanomolar doses of insulin. Using a stripe assay seeded with insulin, neurites were more likely to reject higher doses of insulin. Insulin down-regulated mRNAs of the insulin receptor β subunit and up-regulated levels of GSK-3β, both potential mechanisms of insulin resistance, while down-regulating the protein expression of pAkt and pGSK-3β. Overall, these studies identify neuronal nuclear targeting of insulin and evidence for insulin-induced resistance to its trophic properties. The findings have implications for the understanding of the actions of insulin in the treatment of diabetes and neurological disorders.
Databáze: OpenAIRE
Externí odkaz: